Project Summary/Abstract In response to RFA-RM-17-028, we propose to investigate the impact of behavioral strategies for reducing stress reactivity in adults with opioid use disorder. Opioid misuse has reached an epidemic level in the United States, with over 12.5 million people misusing prescription opioids and over 900,000 using heroin in 2015. In 2015, over 33,000 people died from opioid overdose, continuing the unabated escalation of deaths since the late 1990s. Although treatments such as buprenorphine maintenance have been shown to be effective for the treatment of opioid use disorder, relapse remains highly prevalent. Heightened reactivity to stress (i.e., affective and physiological response to stressors) is robustly associated with risk for relapse; however, existing treatments have little impact on stress reactivity. Accordingly, there is a clear need for novel interventions to reduce stress reactivity in those with opioid use disorder. Consistent with a mechanisms-focused experimental medicine approach to behavior change research, we propose to test the effect of brief cognitive-behavioral affect regulation interventions on (1) affective and physiological markers of reactivity to stress (target engagement), and (2) short-term behavior change (behavioral persistence in the context of stress). Participants will be randomly assigned to either a control condition or one of two brief affect regulation interventions, consisting of either an intentional affect regulation strategy (cognitive reappraisal) or an incidental affect regulation strategy (affect labeling). These two strategies have been shown to yield similar reductions in response to affective stimuli, but require different levels of cognitive resources, and thus represent two distinct approaches to reducing stress reactivity. The first aim is to determine the impact of intentional and incidental affect regulation strategies on reactivity to a stressor relative to a control condition. The second aim is to determine the association between these affect regulation strategies and behavioral tolerance to a stressor. As a secondary aim, we will investigate whether baseline (i.e., pre-intervention) levels of self-regulation are associated with the impact of these affect regulation strategies. Specifically, we will investigate whether those with self-regulatory deficits have a reduced response to affect regulation interventions and whether they respond differently to intentional vs. incidental strategies (e.g., whether those with self-regulatory deficits exhibit greater responding to an incidental affect regulation strategy, which requires fewer cognitive resources). If our hypotheses are supported, this information can be used to inform the development of a full dose of multi-session cognitive-behavioral therapy for improving outcomes among those with opioid use disorder. Critically, because of the relevance of stress reactivity across an array of psychiatric disorders (alcohol use disorder, posttraumatic stress disorder), these findings may also have implications for behavior change for other mental health conditions.